Nanoscale assembly of amyloid oligomers at physiologically relevant conditions
淀粉样蛋白寡聚物在生理相关条件下的纳米级组装
基本信息
- 批准号:10733250
- 负责人:
- 金额:$ 44.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-25 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AgingAlzheimer&aposs DiseaseAlzheimer&aposs disease therapyAmyloidAmyloid ProteinsAmyloid beta-42Amyloid beta-ProteinBrainCalciumCatalysisCellsCellular MembraneCholesterolComputer ModelsDataDevelopmentDiagnosticDiseaseDissociationEventExperimental ModelsFatty AcidsFoundationsFutureGanglioside GM1GoalsHomeostasisIn VitroKnowledgeLipidsMediatingMembraneMembrane LipidsMembrane MicrodomainsMicroscopicMicrotubulesMissionModelingMolecularMolecular ConformationMutationNerve DegenerationNeurodegenerative DisordersParkinson DiseasePathway interactionsPeptide Initiation FactorsPhospholipidsPhysiologicalPreventionPreventivePreventive measurePreventive therapyProcessPropertyProteinsPublic HealthResearchRoleSphingomyelinsSurfaceSynapsesTestingTherapeuticTherapeutic InterventionTranslatingTubeUnited States National Institutes of HealthWorkabeta accumulationabeta oligomeramyloid formationcatalystdrug discoveryexperimental studyimprovedin vivoinsightmembrane modelmodel developmentmolecular dynamicsmolecular modelingmonomernanonanoassemblynanomolarnanoscalenanosizedneurotoxicnovelnovel strategiespreventpreventive interventionprogramsprotein aggregationself assemblytau-1theoriestranslational study
项目摘要
Assembly of nanoaggregates by amyloid beta (Ab), as a widely accepted model for development of Alzheimer’s disease
(AD), has recently gained additional support. The vast majority of in vitro studies are performed at Ab concentrations
several orders higher than the physiologically relevant concentrations of Aβ in the brain; no nanoscale assembly of Aβ is
observed at the low nanomolar concentration found in vivo. This suggests that the assembly of Aβ in vivo utilizes pathways
different from those used in vitro. We discovered that spontaneous assembly of Aβ42 oligomers from monomers, within
the physiological concentration range, can occur by utilizing the on-surface aggregation mechanism. Here, the surface acts
as a catalyst for the aggregation process. We developed a model that explains the surface catalytic effect of the amyloid
aggregation from monomers, at low nanomolar concentrations. In the model, the membrane effectively catalyzes amyloid
aggregation by stabilizing aggregation-prone conformations. According to our preliminary data, this process depends on the
membrane composition; therefore, we hypothesize that the change of the membrane composition is the factor that defines
the assembly of the disease-prone Aβ aggregates. This hypothesis is supported by findings that aging is associated with
changes in lipid composition and alterations of fatty acids at the level of lipid rafts were found in the early stage of AD. A
thorough testing of this hypothesis is the major goal of this application. The rationale is that understanding the fundamental
mechanisms of membrane-mediated Aβ nanoscale assembly will guide the development of practical approaches to control
the aggregation process. The objective of this proposal is to characterize the on-surface formation of Aβ nanoscale
assemblies, identify the aggregation-prone composition of cellular membranes, and develop a quantitative molecular model
for future use in translational studies. Guided by strong preliminary data, we will test our central hypothesis through the
following three specific aims: Aim 1: Characterize the nanoscale assembly processes of Ab monomers catalyzed by cellular
membranes with different lipid compositions. Aim 2: Evaluate contributions of free lipids on the membrane catalysis of
amyloid nanoassembly. Aim 3: Develop a molecular model for the membrane catalysis phenomenon using multi-scale
theoretical and computational approaches. Aim 1 is focused on testing our hypothesis that the lipid composition of the
membrane bilayer is the defining factor in spontaneous aggregation of Ab proteins at physiological concentrations. Under
Aim 2, we will test the hypothesis that free lipids contribute further to the membrane catalysis of amyloid aggregation. Aim
3 proposes the use of various theoretical approaches and computer modeling to gain structural insights into the molecular
mechanism of aggregation by the cellular membrane. The predictions of the theory will be tested under Aims 1 and 2. The
proposed research plan, combining experimental studies with extensive computational modeling, will provide a molecular
model for the Aβ nanoassembly process catalyzed by membranes at physiological concentrations of monomers. The
development of preventative measures for the interaction of monomeric amyloids with membranes can help to control the
aggregation process. This is a paradigm shift, which opens prospects for the development of new efficient treatments, early
diagnostics, and preventive therapies for AD.
β淀粉样蛋白(Ab)组装纳米聚集体,作为阿尔茨海默病发展的广泛接受模型
(AD),最近获得了更多的支持。绝大多数体外研究均在Ab浓度下进行
比大脑中Aβ的生理相关浓度高几个数量级;没有Aβ的纳米级组装,
在体内发现的低纳摩尔浓度下观察到。这表明Aβ在体内的组装利用了
与体外使用的不同。我们发现,Aβ42寡聚体从单体中自发组装,
生理浓度范围,可以通过利用表面聚集机制来实现。在这里,表面
作为聚集过程的催化剂。我们开发了一个模型,解释了淀粉样蛋白的表面催化作用,
在低纳摩尔浓度下,单体聚集。在模型中,膜有效地催化淀粉样蛋白
通过稳定易于聚集的构象来抑制聚集。根据我们的初步数据,这一过程取决于
膜组成;因此,我们假设膜组成的变化是定义
易患病的Aβ聚集体的组装。这一假设得到了以下研究结果的支持:
在AD的早期阶段,脂筏水平的脂质组成和脂肪酸的改变就已存在。一
本申请的主要目的是彻底检验这一假设。基本原理是,
膜介导的Aβ纳米级组装的机制将指导实际方法的发展,
聚合过程。该提案的目的是表征Aβ纳米尺度的表面形成
组装,确定细胞膜的聚集倾向的组成,并建立定量分子模型
以备将来用于翻译研究。在强有力的初步数据的指导下,我们将通过
以下三个具体目标:目标1:表征由细胞催化的Ab单体的纳米级组装过程
不同脂质成分的膜。目的2:评价游离脂质对膜催化的贡献,
淀粉样蛋白纳米组装体目标3:利用多尺度技术建立膜催化现象的分子模型
理论和计算方法。目的1是集中在测试我们的假设,即脂质组成的
膜双层是生理浓度下Ab蛋白自发聚集的决定因素。下
目的2,我们将测试的假设,游离脂质有助于进一步的膜催化淀粉样蛋白聚集。目的
3提出了使用各种理论方法和计算机建模来获得分子结构的见解,
通过细胞膜聚集的机制。该理论的预测将在目标1和2下得到检验。的
拟议的研究计划,结合实验研究与广泛的计算建模,将提供一个分子
在生理浓度的单体下,膜催化的Aβ纳米组装过程的模型。的
开发单体淀粉样蛋白与膜相互作用的预防措施有助于控制
聚合过程。这是一个范式转变,为开发新的有效治疗方法开辟了前景,
AD的诊断和预防性治疗。
项目成果
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YURI L LYUBCHENKO其他文献
YURI L LYUBCHENKO的其他文献
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{{ truncateString('YURI L LYUBCHENKO', 18)}}的其他基金
Bioscope II - AFM system for Nanoimaging Core Facility
Biscope II - 用于纳米成像核心设施的 AFM 系统
- 批准号:
7212020 - 财政年份:2007
- 资助金额:
$ 44.14万 - 项目类别:
Nanomedicine Center for Protein Deposition Diseases(RMI)
蛋白质沉积疾病纳米医学中心(RMI)
- 批准号:
6931370 - 财政年份:2004
- 资助金额:
$ 44.14万 - 项目类别: